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CHAPTER
11
Mood Disorders
III Description
of mood disorders
III The bipolar spectrum
III Can unipolar depression
be distinguished
from bipolar depression?
II1IIAre mood disorders progressive?
III Neurotransmitters
and circuits in mood disorders
• Noradrenergic
neurons
iii Monoamine
interactions:
NE regulation of 5HT release
" Monoamine
interactions:
5HT regulation of NE and DA release
III The monoamine
hypothesis of depression
III The monoamine
hypothesis,
monoamine
III Symptoms
and circuits
III Symptoms
and circuits in mania
III Genes and neuroimaging
receptors, and gene expression
in depression
in mood disorders
III Summary
mania, or both. Included are descriptions of a wide variety of mood
Thisdepn;:ssion,
chapterthat
discusses
disorders
characterized
by abnormalities
of mood:
disorders
occur over
a broad
clinical spectrum.
Also included
is an namely,
analysis
of how abnormalities in regulation of the trimonoaminergic neurotransmitter system comprising the three monoamine neurotransmitters norepinephrine (NE; also called noradrenaline, or NA), dopamine (DA), and serotonin (also called S-hydroxytryptamine, or
SHT) - are hypothesized to explain the biological basis of mood disorders. The approach
taken here is to deconstruct each mood disorder into its component symptoms, followed by
matching each symptom to hypothetically malfunctioning brain circuits, each regulated by
one or more of the neurotransmitters within the trimonoaminergic neurotransmitter system. The genetic regulation and neuroimaging of these hypothetically malfunctioning brain
circuits are also briefly mentioned. The discussion of symptoms and circuits in this chapter
is intended to set the stage for understanding the pharmacological concepts underlying the
mechanisms of action and use of antidepressants and mood-stabilizing drugs reviewed in
the following two chapters (Chapters 12 and 13).
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Mood Chart
mania
II1IIII1II
II1II-
-
HYPOMANIA- -
euthymia
(normal mood)
~-<
II1II
II1II_
----
~
{1~)~ }
- - - - - - - - - - - DYSTHYMIA - - - - - - - - - - -
depression
FIGURE 11-1 Mood chart. Disorders of mood can be mapped on a mood chart to track the course of illness,
identify phase of illness, and aid in differential diagnosis. As shown in this chart, mood can range from mania at
the top, to hypomania, to euthymia (normal mood) in the middle, and to dysthymia and depression at the bottom.
Clinical descriptions and criteria for the diagnosis of disorders of mood are mentioned
only in passing. The reader should consult standard reference sources for this material.
Here we discuss how the discovery of various neurotransmitters and brain circuits has
influenced the understanding of symptoms in mood disorders. The goal of this chapter is
to outline current ideas about the clinical and biological aspects of mood disorders in order
to prepare the reader to understand the various treatments for these disorders discussed in
later chapters.
Description of mood disorders
Disorders of mood are often called affective disorders, since affect is the external display of
mood or emotion which is, however, felt internally. Depression and mania are often seen
as opposite ends of an affective or mood spectrum. Classically, mania and depression are
"poles" apart, thus generating the terms "unipolar" depression (i.e., as in patients who just
experience the down or depressed pole) and "bipolar" [i.e., as in patients who at different
times experience either the up (manic) pole or the down (depressed) pole]. In practice,
however, depression and mania may occur simultaneously, in which case a "mixed" mood
state exists. Mania may also occur in lesser degrees, known as "hypomania"; or a patient
may switch so quickly between mania and depression that it is called "rapid cycling."
Mood disorders can be usefully visualized not only to distinguish different mood disorders from one another but also to summarize the course of illness for individual patients
by showing them their disorders mapped onto a mood chart. Thus, mood ranges from
hypomania to mania at the top, to euthymia (or normal mood) in the middle, to dysthymia
and depression at the bottom (Figure 11-1). Mood abnormalities for the major diagnostic
entities are summarized in Figure 11-2 and shown in more detail in Figures 11-3 through
11-29.
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manic
•..~'
Manic Episode
Mania (abnormally elevated, expansive,
or irritable mood) plus 3 or 4 other symptoms
•. -1- __
Major Depressive Episode
Depressed mood or loss of interest coupled
with four other symptoms
-_!III
~ IDYSTHYMiA;
- •• I" .1'
Hypomanic Episode
Hypomania (elevated, expansive, or irritable mood,
less severe and shorter duration than mania)
plus 3 or 4 other symptoms
Mixed Episode
Meets criteria for both a manic episode
and a major depressive episode
FIGURE 11-2 Mood episodes. Bipolar disorder is generally characterized by four types of illness episodes:
manic, major depressive, hypomanic, and mixed. A patient may have any combination of these episodes over the
course of illness; subsyndromal manic or depressive episodes also occur during the course of illness, in which
case there are not enough symptoms or the symptoms are not severe enough to meet the diagnostic criteria for
one of these episodes. Thus the presentation of mood disorders can vary widely.
Major Depression
Single Episode or Recurrent
IIIiII
...,
RIB
RIB
RIB
-
•••
-
•••
RIB
single episode
RIB
HYPOMANIA
l1li
••
!IIIII
••
RIB
RIB
RIB
_
recurrent
FIGURE 11-3 Major depression. Major depression is the most common mood disorder and is defined by the
occurrence of at least a single major depressive episode, aithough most patients will experience recurrent
episodes.
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Dysthymia
~I'"
--------------
•••••••••••••••••••••••••••••••••HYPOMANIA'" •••••••••••••••••••••••••••••••
----~----2+ years
•
FIGURE 11-4 Dysthymia. Dysthymia is a less severe form of depression than major depression but long-lasting
(over two years in duration) and is often unremitting.
The most common and readily recognized mood disorder is major depression (Figure 11-3) as a single episode or recurrent episodes. Dysthymia is a less severe but often
longer-lasting form of depression (Figure 11-4). Patients with a major depressive episode
who have poor inter-episode recovery, only to the level of dysthymia, which is then
followed by another episode of major depression, are sometimes said to have "double
depression," alternating between major depression and dysthymia but not remitting (Figure 11-5).
Bipolar I patients have full-blown manic episodes and! or mixed episodes of full mania
plus simultaneous full depression, often followed by a full depressive episode (Figure 11-6).
When mania recurs at least four times a year, it is called rapid cycling (Figure 11-17 A).
Bipolar I patients can also have rapid switches from mania to depression and back (Figure
11-17B). By definition, this occurs at least four times a year, but it can happen much more
frequently than that.
Bipolar II disorder is characterized by at least one hypomanic episode and one full
depressive episode (Figure 11-8). Cyclothymic disorder is characterized by mood swings
less severe than full mania and full depression but still waxing and waning above and below
the boundaries of normal mood (Figure 11-9). There may be lesser degrees of variation
from normal mood that are stable and persistent, including both depressive temperament
(below normal mood but not a mood disorder) (Figure 11-10) and hyperthymic temperament (above normal mood but also not a mood disorder) (Figure 11-11). Temperaments
are lifelong personality styles of responding to environmental stimuli; they can be heritable
patterns present early in life and persisting thereafter and include such independent personality dimensions as novelty seeking, harm avoidance, and conscientiousness. Some patients
may have mood-related temperaments that may render them vulnerable to mood disorders,
especially bipolar spectrum disorders, later in life.
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Double Depression
,
,
____
r::.
:_
HYPOMAN':~- - - - - - - - - --
,
,
---,
:~
2+ years
6-24 months
FIGURE 11-5 Double depression. Patients with unremitting dysthymia who also experience the superimposition
of one or more major depressive episodes are described as having double depression. This is also a form of
recurrent major depressive episodes with poor inter-episode recovery.
Bipolar I
Manic or Mixed Episode ± Major Depressive Disorder
--------mixed
- - - - - -.
- ••
--
- DYSTHYM'~· ••• - -.
FIGURE 11-6 Bipolar I disorder. Bipolar I disorder is defined as the occurrence of at least one manic or mixed
(full mania and full depression simultaneously) episode. Patients with bipolar I disorder typically experience major
depressive episodes as well, although this is not necessary for the bipolar I diagnosis.
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Rapid Cycling Mania
A
FIGURE 11-7A Rapid cycling mania. The course of bipolar disorder can be rapid cycling, which means that at
least four episodes occur within a one-year period. This can manifest itself as four distinct manic episodes, as
shown here. Many patients with this form of mood disorder experience switches much more frequently than four
times a year.
Rapid Cycling Switches
B
FIGURE 11-78 Rapid cycling switches. A rapid cycling course (at least four distinct mood episodes within one
year) can also manifest as rapid switches between manic and depressive episodes.
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Bipolar II
Depressive and Hypomanic Episodes
- - - - - - - - - - - HYPOMANIA - ,...
-,
- - - - - .~ - - .J - -
DYSTHYMIA - - - - - - - - - - -
FIGURE 11-8 Bipolar II disorder. Bipolar II disorder is defined as an illness course consisting of one or more
major depressive episodes and at least one hypomanic episode.
Cyclothymic Disorder
FIGURE 11-9 Cyclothymic disorder. Cyclothymic disorder is characterized by mood swings between hypomania
and dysthymia but without any full manic or major depressive episodes.
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Depressive Temperament
-------.---
HYPOMANIA'"
••••r- ••••
HYPERTHYMIC
TEMPERAMENT,
~~
'"" •••"'" •••- •••••••••••••••••
••••••
,., ••••••.
""
••••
""
•
rr-
{<) ~ }
nFPRF~~!\f1=
TEMPERAMENT
•••••••••••••"'" ••••••••••••••••••• DYSTHYMIA - •••••• - ••• - III ••• - ••• -
FIGURE 11-10
Depressive temperament.
Not all mood variations are pathological. Individuals with depressive
temperament may be consistently sad or apathetic but do not meet the criteria for dysthymia and do not
necessarily experience any functional impairment. However, individuals with depressive temperament may be at
greater risk for the development of a mood disorder later in life.
Hyperthymic Temperament
•••••••••••••••••••••••••••••••••• HYPOMANIA'"
••• III - III ••• III ••• III III •••
HYPERTHYMiC
••••
•••
•••••••••••••••••••••••••••••••••
EJ
•••• DEPRESSiVE
TEMPERAMENT
*&
•••
DYSTHYMIA •••••••••••••••••••••••••••••••••
FiGURE 11-11 Hyperthymic temperament. Hyperthymic temperament, in which mood is above normal but not
pathological, includes stable characteristics such as extroversion, optimism, exuberance, impulsiveness,
overconfidence, grandiosity, and lack of inhibition. Individuals with hyperthymic temperament may be at greater
risk for the development of a mood disorder later in life.
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The Bipolar Spectrum
11-12 Bipolarspectrum. The onlyformalunique bipolardiagnosesidentifiedin the Diagnostic and
are bipolarI, bipolarII,and cyclothymic
Manual of Mental Disorders, fourth edition(DSM-IV),
disorder,with all other presentationsthat includemoodsymptomsabovethe normalrange lumpedtogetherin a
singlecategorycalled "not otherwisespecified(NOS)."However,there is a hugevariationin the presentationof
patientswithinthis bipolarNOScategory.It may be moreuseful,instead, to thinkof these patients as belonging
to a bipolarspectrumand to identifysubcategoriesof presentations,as has been done by Akiskaland other
expertsand as illustratedin the nextseveralfigures.
FIGURE
Statistical
The bipolar spectrum
From a strict diagnostic point of view, our discussion of mood disorders might now be
complete. However, there is growing recognition that many or even most patients seen
in clinical practice may have a mood disorder that is not well described by the categories
outlined above. Formally, they would be called "not otherwise specified" or "NOS," but
this creates a huge single category for many patients that belies the richness and complexity of their symptoms. Increasingly, such patients are seen as belonging in general to the
"bipolar spectrum" (Figure 11-12) and, in particular, to one of several additional descriptive
categories proposed by experts such as Akiskal (Figures 11-12 through 11-21).
Two forms of mood disorder often considered to be "not quite bipolar" may include
bipolar % and bipolar % (Figures 11-13 and 11-14). Bipolar % (or 0.25) could designate an
unstable form of unipolar depression that responds sometimes rapidly but in an unsustained
manner to antidepressants. Such an uneven response is sometimes called antidepressant
"poop out" (Figure 11-13). These patients have unstable mood but not a formal bipolar
disorder, yet they can sometimes benefit from mood-stabilizing treatments added to robust
antidepressant treatments. Bipolar % (or 0.5) may indicate a type of "schizo bipolar" disorder,
also sometimes called schizo affective disorder, combining positive symptoms of psychosis
with manic, hypomanic, and depressive episodes (Figure 11-14). The placement of these
patients within the bipolar spectrum can provide a rationale for treating them with mood
stabilizers and atypical antipsychotics as well as antidepressants.
Although patients with protracted or recurrent hypomania without depression are not
formally diagnosed as having bipolar II disorder, they are definitely part of the bipolar
spectrum and may benefit from the mood stabilizers studied mostly in bipolar I disorder (Figure 11-15). Eventually such patients often develop a major depressive episode,
and their diagnosis then changes to bipolar II disorder. In the meantime, they can be
treated for hypomania while being vigilantly watched for the onset of a major depressive
episode.
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Bipolar %
Depressive Episodes but Rapid Poop Out to Antidepressants
FIGURE 11-13 Bipolar %. Some patients may present only with depressive symptoms yet exhibit rapid but
unsustained response to antidepressant treatment (sometimes called rapid "poop out"). Although such patients
may have no spontaneous mood symptoms above normal, they potentially could benefit from mood-stabilizing
treatment. This presentation may be termed bipolar 0.25 (or bipolar 1/4).
Bipolar %
Schizobipolar Disorder
Positive Symptoms of Psychosis with Manic, Hypomanic, and Depressive Episodes
/
hypomania + positive symptoms
normal mood +
"
positive symptoms
FIGURE 11-14
Bipolar 1/2. Bipolar 1/2 has been described as schizobipolar disorder, which combines positive
symptoms of psychosis with manic, hypomanic, and depressive episodes.
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Bipolar
1%
Protracted Hypomania Without Depression
FIGURE 11-15
Bipolar 11/2. A formal diagnosis of bipolar II disorder requires the occurrence of not only
hypomanic episodes but also depressive episodes. However, some patients may experience recurrent hypomania
without having experienced a depressive episode - a presentation that may be termed bipolar I 1/2_ These patients
may be at risk of eventually developing a depressive episode and are candidates for mood stabilizing treatment,
although no treatment is formally approved for this condition.
Bipolar II 1;2 is the designation for patients with cyclothymic temperament who develop
major depressive episodes (Figure 11-16). Many patients with cyclothymic temperament
are just considered "moody" and do not consult professionals until they experience a full
depressive episode. It is important to recognize patients in this part of the bipolar spectum
because treatment of their major depressive episodes with antidepressant monotherapy may
actually cause increased mood cycling or even induce a full manic episode, just as can happen
in patients with bipolar I or II depressive episodes.
In fact, patients who develop a manic or hypomanic episode on an antidepressant
are sometimes called bipolar III (Figure 11-17). According to formal diagnostic criteria,
however, when an antidepressant causes mania or hypomania, the diagnosis is not bipolar
disorder but rather "substance-induced mood disorder." Many experts disagree with this
designation and feel that patients who have a hypomanic or manic response to an antidepressant do so because they have a bipolar spectrum disorder and can be more appropriately
diagnosed as bipolar III disorder (Figure 11-17) until they experience a spontaneous manic
or hypomanic episode while taking no drugs, at which point their diagnosis would be bipolar I or II, respectively. The bipolar III designation is helpful in the meantime, reminding
clinicians that such patients are not good candidates for antidepressant monotherapy.
A variant of bipolar III disorder has been called bipolar III 1/2 to designate a type of
bipolar disorder associated with substance abuse (Figure 11-18). Although some of these
patients can utilize substances of abuse to treat depressive episodes, others have previously
experienced natural or drug-induced mania and take substances of abuse to induce mania.
This combination of a bipolar disorder with substance abuse is a formula for chaos and can
often be the story of a patient prior to seeking treatment from a mental health professional.
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Bipolar
11112
Depressive Episodes With Cyclothymic Temperament
FIGURE 11-16 Bipolar 111/2' Patients may present with a major depressive episode in the context of
cyclothymic temperament, which is characterized by oscillations between hyperthymic or hypomanic states
(above normal) and depressive or dysthymic states (below normal) upon which a major depressive episode
intrudes (bipolar II 1/2). Individuals with cyclothymic temperament who are treated for the major depressive
episodes may be at increased risk for antidepressant-induced mood cycling.
Bipolar III
Depressive Episodes with Antidepressant-Induced
Hypomania
FIGURE 11-17 Bipolar III. Although the Diagnostic and Statistical Manual of Mental Disorders, fourth edition
(DSM-IV), defines antidepressant-induced (hypo)mania as a substance-induced mood disorder, some experts
believe that individuals who experience substance-induced (hypo)mania are actually predisposed to these mood
states and thus belong to the bipolar spectrum (bipolar III).
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Bipolar
111%
Bipolar Disorder, Substance Abuse
----
-
-
""" -
-----
••• -
-
""" Ii••••••••
DySTHyMIA •••
--
'
\
substance
.
abuse
FIGURE 11-18 Bipolar 1111/2' Bipolar1111/2 is bipolardisorderwithsubstance abuse, in which the substance
abuse is associated witheffortsto achievehypomania.Such patientsshould be evaluatedcloselyto determineif
(hypo)maniahas everoccurredin the absence of substance abuse.
Bipolar IV disorder is the association of depressive episodes with a preexisting hyperthymic temperament (Figure 11-19). Patients with hyperthymia are often sunny, optimistic,
high-output, successful individuals whose temperaments have been stable for years but who
then suddenly collapse into a severe depression. In such cases, it may be useful to be vigilant
to the need for more than antidepressant monotherapy if the patient is unresponsive to such
treatment or develops rapid cycling, hypomanic, or mixed states in response to antidepressants. Despite not having a formal bipolar disorder, such patients may respond best to mood
stabilizers.
Bipolar V disorder is depression with mixed hypomania (Figure 11-20). Formal diagnostic criteria for mixed states require full expression of both depression and mania simultaneously. In the real world, however, many depressed patients can have additional symptoms
that qualifY as only hypomania or even just a few or mild manic symptoms. Depression
coexisting with full hypomania is represented in Figure 11-20 and requires mood stabilizer
treatment, not antidepressant monotherapy.
Related states include mood states where full diagnostic criteria are not reached; these
can range from full mixed states [both full mania diagnostic criteria (M) and full depression
diagnostic criteria (D)] to depression with hypomania or only a few hypomanic symptoms
(mD), as already discussed. In addition, other combinations of mania and depression range
from full mania with only a few depressive symptoms (Md, sometimes also called "dysphoric"
mania), to subsyndromal but unstable states characterized by some symptoms of both mania
and depression but not diagnostic of either (md) (Table 11-1). All of these states differ from
unipolar depression and belong in the bipolar spectrum; they may require treatment with the
same agents used to treat bipolar lor II disorder, with appropriate caution for antidepressant
monotherapy. The fact that a patient is depressed does not mean that he or she should start
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Bipolar IV
Depressive Episodes With Hyperthymic Temperament
FIGURE 11-19
Bipolar IV. Bipolar IV is seen in individuals with long-standing and stable hyperthymic
temperament into which a major depressive episode intrudes. Individuals with hyperthymic temperament who
are treated for depressive episodes may be at increased risk for antidepressant-induced mood cycling and may
instead respond better to mood stabilizers.
Bipolar V
Depression With Mixed Hypomania
FIGURE 11-20
Bipolar V. Bipolar V is defined as major depressive episodes with hypomanic symptoms
occurring during the major depressive episode but without the presence of discrete hypomanic episodes. Because
the symptoms do not meet the full criteria for mania, these patients would not be considered to have a full mixed
episode, but they nonetheless exhibit a mixed presentation and may require mood stabilizer treatment as opposed
to antidepressant monotherapy.
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TABLE 11-1
Mixed States of Mania and Depression
Description
Designation
Comment/Other Names
DSM-IV mixed
MD
mD
mD
Full diagnostic criteria for both mania and depression
Bipolar V
Bipolar NOS
Md
Dysphoric mania
md
Prodrome or presymptomatic or state of incomplete
remIsSIon
Depression with hypomania
Depression with some manic
symptoms
Mania with some depressive
symptoms
Subsyndromal mania with
subsyndromal depression
Bipolar VI
Bipolarity in the Setting of Dementia
FIGURE 11-21
Bipolar VI. Another subcategory within the bipolar spectrum may be "bipolarity in the setting of
dementia," termed bipolar VI. Mood instability here begins late in life, followed by impaired attention, irritability,
reduced drive, and disrupted sleep. The presentation may initially appear to be attributable to dementia or be
considered unipolar depression, but it is likely to be exacerbated by antidepressants and may respond to mood
stabilizers.
treatment with an antidepressant. Patients with mixed states of depression and mania may
be particularly vulnerable to the induction of activation, agitation, rapid cycling, dysphoria,
hypomania, mania, or suicidality when treated with antidepressants, particularly without
the concomitant use of a mood stabilizer or an atypical antipsychotic.
Finally, bipolar VI disorder (Figure 11-21) represents bipolarity in the setting of dementia, where it can be incorrectly attributed to the behavioral symptoms of dementia rather
than recognized as a comorbid mood state and treated with mood stabilizers and even with
atypical antipsychotics. Many more subtypes of mood disorders can be described within
the bipolar spectrum. The important thing to take away from this discussion is that not all
patients with depression have major depressive disorder requiring treatment with antidepressant monotherapy and that there are many states of mood disorder within the bipolar
spectrum beyond just bipolar I and II disorders.
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What Proportion of Mood Disorders Are Bipolar?
old paradigm
FIGURE 11-22
shifting paradigm
Prevalence of mood disorders. In recent years there has been a paradigm shift in terms of the
recognition and diagnosis of patients with mood disorders. That is, many patients once considered to have major
depressive disorder (old paradigm, left) are now recognized as having bipolar II disorder or another form of bipolar
illness within the bipolar spectrum (shifting paradigm, right).
Can unipolar depression be distinguished from bipolar depression?
One of the important developments in the field of mood disorder in recent years, in fact,
is the recognition that many patients once considered to have major depressive disorder
actually have a form of bipolar disorder, especially bipolar II disorder or one of the conditions within the bipolar spectrum (Figure 11-22). Since symptomatic patients with bipolar
disorder spend much more of their time in the depressed state than in the manic, hypomanic, or mixed state, this means that many depressed patients in the past were incorrectly
diagnosed with unipolar major depression and treated with antidepressant monotherapy
instead of being diagnosed as having a bipolar spectrum disorder and treated first with
lithium, anticonvulsant mood stabilizers, and/or atypical antipsychotics prior to being given
an antidepressant.
Up to half of patients once considered to have a unipolar depression are now considered
to have a bipolar spectrum disorder (Figure 11-22), and although they would not necessarily be good candidates for antidepressant mono therapy, this is often the treatment that
they receive when the bipolar nature of their condition is not recognized. Antidepressant
treatment of unrecognized bipolar disorder may not only increase mood cycling, mixed
states, and conversion to hypomania and mania, as mentioned above, but also contribute
to the increase in suicidality of patients treated with antidepressants, with adults below
twenty-five years of age being at greater risk for antidepressant-induced
suicidality than
older adults, adolescents more at risk than younger adults, and children more at risk than
adolescents.
Thus it becomes important to recognize whether a depressed patient has a bipolar
spectrum disorder or a unipolar major depressive disorder. How can this be done? In reality,
these patients can have identical current symptoms (Figure 11-23), so obtaining the profile
of current symptomatology is obviously not sufficient to distinguish unipolar from bipolar
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TABLE
11-2 Is it unipolar or bipolar depression? Questions to ask
Who's your daddy?
What is your family history of:
- Mood disorder
- Psychiatric hospitalizations
- Suicide
- Anyone who took lithium, mood stabilizers, antipsychotics, antidepressants
- Anyone who received ECT
These can be indications of a unipolar or bipolar spectrum disorder in relatives.
Where's your mama?
Additional history is needed about you from someone close to you, such as your mother or spouse.
Patients may especially lack insight about their manic symptoms and underreport them.
Is It Unipolar or Bipolar Depression?
Identical Current Symptoms
Patient A:
Current Episode
3 Days Ago
7 Days Ago
FIGURE 11-23
Patient B:
Current Episode
Today
3 Days Ago
7 Days Ago
Today
Unipolar versus bipolar depression presentation. The presenting symptoms of a major
depressive episode in bipolar illness (Patient B) may be indistinguishable from those of a major depressive
episode in unipolar depression (Patient A). Thus, the current presentation is not sufficient for making the
differential diagnosis. The additional information needed includes family history, symptom and treatmentresponse history, and feedback from a friend or relative.
depression.
The
answer
may be to ask the two questions
shown
in Table
"Who's your daddy?" and "Where's your mama?"
What this means is "What is your family history?"
since the existence
relative with a bipolar
suggest
spectrum
disorder
can strongly
11-2, namely,
of a first-degree
that the patient
also has a
bipolar spectrum disorder rather than unipolar depression. This also means, "I need to get
additional history from someone else close to you," since patients tend to underreport
their
manic symptoms, and the insight and observations of an outside informant such as a mother
or spouse can give a past history quite different from the one the patient is reporting and
thus help establish
may deny.
a bipolar
spectrum
diagnosis
that patients
themselves
do not perceive or
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Is It Unipolar or Bipolar Depression?
Different Past Symptoms Make the Diagnosis
Patient A:
Current Episode and History
-
-
-
-
- HYPOMANIA
-
-
Patient B:
Current Episode and History
-
•••
-
6 months ago
FIGURE 11·24
today
-
••• -
- DYSTHYMIA
3 years ago
6 months ago
••• -
•••••
today
Unipolar versus bipolar depression history. Patterns of past symptoms as well as treatment·
response history may aid in distinguishing between unipolar and bipolar illness. As shown here, although Patients
A and B both present with major depressive episodes, they have divergent histories that suggest a unipolar illness
for Patient A and a bipolar illness for Patient B.
Pattern of past symptoms can also give a hint as to whether a patient has a bipolar
spectrum depression rather than a unipolar depression, as discussed above and as shown in
Figure 11-24. Thus, prior response to antidepressants, prior hyperthymia or hypomania, can
be hints from past symptoms to help distinguish unipolar from bipolar spectrum depression.
Some hints, but not sufficient for diagnostic certainty, can even come from current symptoms
to suggest a bipolar spectrum depression, such as more time sleeping, overeating, comorbid
anxiety, motor retardation, mood lability, or psychotic or suicidal thoughts (Figure 11-25).
Hints that the depression may be in the bipolar spectrum can come from the course of the
untreated illness prior to the current symptoms, such as early age of onset, high frequency
of depressive symptoms, high proportion of time spent ill, and acute abatement or onset of
symptoms (Figure 11-26). Prior responses to antidepressants that suggest bipolar depression
can be multiple antidepressant failures, rapid recovery, and the activation of side effects such
as insomnia, agitation, and anxiety (Figure 11-27).
Although none of these features can discriminate bipolar depression from unipolar
depression with certainty, the point is to be vigilant to the possibility that what looks like
a unipolar depression might actually be a bipolar spectrum depression when investigated
more carefully, and when response to treatment is monitored.
Are mood disorders progressive?
One of the major unanswered questions about the natural history of depressive illnesses
is whether they are progressive (Figures 11-28 and 11-29). Specifically, it appears that
many more patients in mental health practices have bipolar spectrum illnesses than unipolar illnesses, especially compared to a few decades ago. Is this merely the product of
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Identifying Bipolar Depression:
Hints From Current Symptoms
-
-
-
-
- HYPOMANIA
-
-
-
-
BIPOLAR DEPRESSION
More:
Time sleeping
Overeating
Comorbid anxiety
Motor retardation
Mood lability during episode
Psychotic symptoms
Suicidal thoughts
FIGURE 11-25
Bipolar depression symptoms. Although all symptoms of a major depressive episode can occur
in either unipolar or bipolar depression, some symptoms may present more often in bipolar versus unipolar
depression, providing hints if not diagnostic certainty that the patient has a bipolar spectrum disorder. These
symptoms include increased time sleeping, overeating, comorbid anxiety, psychomotor retardation, mood lability
during episodes, psychotic symptoms, and suicidal thoughts.
Identifying Bipolar Depression:
History
- - •• - •• - - - - - - HYPOMANIA - •• - •• - - - - - - acute abatement
job
change
or onset
of symptoms
job
change
'V
high frequency
FIGURE 11-26
of depressive
episodes.
high proportion
of time spent ill
Identifying bipolar depression: history. Even in the absence of any previous (hypo)manic
episodes, there are often specific hints in the untreated course of illness that suggest depression as part of the
bipolar spectrum. These include early age of onset, high frequency of depressive episodes, high proportion of time
spent ill, acute onset or abatement of symptoms, and behavioral symptoms such as frequent job or relationship
changes.
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Identifying Bipolar Depression:
Response to Antidepressants
worsened
insomnia on antidepressant
-----------
HyPOMANIA •.••- - "recovery"
after <2 weeks
\
multiple antidepressant
FIGURE 11-27
-----1--
failures
Identifying bipolar depression: response to antidepressants.
Treatment-response history,
particularly prior response to antidepressants, may provide insight into whether depression is unipolar or bipolar.
Prior responses that suggest bipolar depression may include multiple antidepressant failures, rapid response to an
antidepressant, and activating side effects such as insomnia, agitation, and anxiety.
Is Major Depressive Disorder Progressive?
______
e __
:-:
---
- HYPOMANIA
--+
--+
.
... - - - - ... recurrent
poor inter-episode
recovery
FIGURE 11-28
--
-
bipolar
spectrum
treatment
resistance
Is major depressive disorder progressive? A currently unanswered question is whether mood
disorders are progressive. Does undertreatment of unipolar depression, in which residual symptoms persist and
relapses occur, lead to progressive worsening of illness, such as more frequent recurrences and poor inter-episode
recovery? And can this ultimately progress to a bipolar spectrum condition and finally treatment resistance?
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Essential Psychopharmacology
Is Bipolar Disorder Progressive?
......•
""
""
discrete manic
and depressive
episodes
FIGURE 11-29
-
-
.
mixed and
dysphoric
episodes
111-
rapid cycling
and treatment
resistance
Is bipolar disorder progressive? There is some concern that undertreatment of discrete manic
and depressive episodes may progress to mixed and dysphoric episodes and finally to rapid cycling and treatment
resistance.
changing diagnostic criteria, or does unipolar depression progress to bipolar depression
(Figure 11-28)?
A corollary of this question is whether chronic and widespread undertreatment of
unipolar depression, allowing residual symptoms to persist and relapses and recurrences to
occur, results first in more rapidly recurring episodes of major depression, then in poor interepisode recovery, then progression to a bipolar spectrum condition, and finally to treatment
resistance (Figure 11-28). Many treatment-resistant mood disorders in psychiatric practices
have elements of bipolar spectrum disorder that can be identified, and many of these patients
require treatment with more than antidepressants or with mood stabilizers and atypical
antipsychotics instead of antidepressants. This is discussed in detail in Chapter 12, which
covers antidepressants, and in Chapter 13, which covers mood stabilizers.
For patients already diagnosed with bipolar disorder, there is similar concern that the
disorder may be progressive, especially without adequate treatment. Thus, discrete manic
and depressive episodes may progress to mixed and dysphoric episodes and finally to rapidcycling instability and treatment resistance (Figure 11-29). The hope is that recognition
and treatment of both unipolar and bipolar depressions, causing all symptoms to remit for
long periods of time, might prevent progression to more difficult states. This is not proved
but is a major hypothesis in the field at present.
In the meantime, practitioners must decide whether to commit "sins of omission" and
be conservative with the diagnosis of bipolar spectrum disorder, thus erring on the side of
undertreatment, or "sins of commission," thus overdiagnosing and overtreating symptoms
in the hope that this will prevent disease progression and "diabolical learning" in brain
circuits, as discussed in Chapter 8 and illustrated in Figures 8-4 through 8-7.
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Neurotransmitters
and circuits in mood disorders
Three principle neurotransmitters have long been implicated in both the pathophysiology and treatment of mood disorders. They are norepinephrine, dopamine, and serotonin
and comprise what is sometimes called the "trimonoaminergic" neurotransmitter system.
These three monoamines often work in concert. Many of the symptoms of mood disorders
are hypothesized to involve dysfunction of various combinations of these three systems.
Essentially all known treatments for mood disorders act on one or more of these three
systems.
We have extensively discussed the dopamine system in Chapter 9 and illustrated it in
Figures 9-18 to 9-24. We have extensively discussed the serotonin system in Chapter 10
and illustrated it in Figures 10-15 to 10-20. Here we introduce both the norepinephrine
system and also some interactions among these three monoaminergic neurotransmitter
systems, showing how they interregulate one another. Although other neurotransmitter
systems are undoubtedly involved in mood disorders, most is known about the links between
trimonoaminergic neurotransmitters and mood disorders, so these neurotransmitters are
emphasized here. New therapeutics based on glutamate and neurokinins are discussed briefly
in Chapters 12 and 13. Neurotransmitters and hormones of the hypothalamic-pituitaryadrenal (HPA) axis are discussed briefly in Chapter 14, on anxiety and stress.
Noradrenergic
neurons
The noradrenergic neuron utilizes norepinephrine (noradrenaline) as its neurotransmitter.
Norepinephrine is synthesized, or produced, from the precursor amino acid tyrosine, which
is transported into the nervous system from the blood by means of an active transport
pump (Figure 11-30). Once inside the neuron, the tyrosine is acted on by three enzymes in
sequence: first, tyrosine hydroxylase (TO H), the rate-limiting and most important enzyme
in the regulation ofNE synthesis. Tyrosine hydroxylase converts the amino acid tyrosine into
dopa. The second enzyme then acts, namely, dopa decarboxylase (DDC), which converts
dopa into dopamine (DA). DA itselfis a neurotransmitter in dopamine neurons, as discussed
in Chapter 9 and illustrated in Figure 9-18. However, for NE neurons, DA isjust a precursor
ofNE. In fact the third and final NE synthetic enzyme, dopamine beta hydroxylase (DBH),
converts DA into NE. NE is then stored in synaptic packages called vesicles until it is
released by a nerve impulse (Figure 11-30).
NE action is terminated by two principal destructive or catabolic enzymes that turn NE
into inactive metabolites. The first is monoamine oxidase (MAO) A or B, which is located
in mitochondria in the presynaptic neuron and elsewhere (Figure 11-31). The second is
catechol-O-methyl-transferase
(COMT), which is thought to be located largely outside of
the presynaptic nerve terminal (Figure 11-31).
The action ofNE can be terminated not only by enzymes that destroy NE but also by
a transport pump for NE that prevents NE from acting in the synapse without destroying
it (Figure 11-31). In fact, such inactivated NE can be restored for reuse in a later neurotransmitting nerve impulse. The transport pump that terminates synaptic action of NE is
sometimes called the "NE transporter" or "NET" and sometimes the "NE reuptake pump."
This NE reuptake pump is located on the presynaptic noradrenergic nerve terminal as part
of the presynaptic machinery of the neuron, where it acts like a vacuum cleaner, whisking NE out of the synapse, off the synaptic receptors, and stopping its synaptic actions.
Once inside the presynaptic nerve terminal, NE can either be stored again for subsequent
reuse when another nerve impulse arrives or it can be destroyed by NE-destroying enzymes
(Figure 11-31).
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Essential Psychopharmacology
Norepinephrine
Is Produced
tyrosine
transporter
\
TYR
1
~
FIGURE 11-30
Norepinephrine
NE (norepinephrine)
is produced. Tyrosine, a precursor to norepinephrine (NE), is taken up into NE
nerve terminals via a tyrosine transporter and converted into dopa by the enzyme tyrosine hydroxylase (TOH).
Dopa is then converted into dopamine COA)by the enzyme dopa decarboxylase (DOC). Finally, DA is converted
into NE by dopamine beta hydroxylase COSH). After synthesis, NE is packaged into synaptic vesicles via the
vesicular monoamine transporter (VMAT2) and stored there until its release into the synapse during
neurotransmission.
The noradrenergic neuron is regulated by a multiplicity of receptors for NE (Figure
11-32). The norepinephrine transporter or NET is one type of receptor, as is the vesicular
monoamine transporter (VMAT2), which transports NE in the cytoplasm of the presynaptic
neuron into storage vesicles (Figure 11-32). NE receptors are classified as alpha lA, 1B,
1C or alpha 2A, 2B, or 2C, or as beta 1, beta 2, or beta 3. All can be postsynaptic, but
only alpha 2 receptors can act as presynaptic autoreceptors (Figures 11-32 through 11-34).
Postsynaptic receptors convert their occupancy by norepinephrine at alpha lA, B, or C;
alpha 2A, B, or C; or beta 1,2, or 3 receptors into physiological functions and ultimately
into changes in signal transduction and gene expression in the postsynaptic neuron (Figure
11-32).
Presynaptic alpha 2 receptors regulate norepinephrine release, so they are called "autoreceptors" (Figures 11-32 and 11-33). Presynaptic alpha 2 autoreceptors are located both on
the axon terminal (i.e., terminal alpha 2 receptors; Figures 11-32 and 11-33) and at the
cell body (soma) and nearby dendrites; thus, these latter alpha 2 presynaptic receptors are
called somatodendritic alpha 2 receptors (Figure 11-34). Presynaptic alpha 2 receptors are
important because both the terminal and somatodendritic alpha 2 receptors are autoreceptors. That is, when presynaptic alpha 2 receptors recognize NE, they turn off further release
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Norepinephrine Action Is Terminated
</
l>
~~
MAO-A or B
destroys NE
FIGURE 11-31
Norepinephrine's
action is terminated.
@) @
~
Norepinephrine's action can be terminated through
multiple mechanisms. Dopamine can be transported out of the synaptic cleft and back into the presynaptic neuron
via the norepinephrine transporter (NET), where it may be repackaged for future use. Alternatively, norepinephrine
may be broken down extracellularly via the enzyme catechol-O-methyl-transferase (COMT). Other enzymes that
break down norepinephrine are monoamine oxidase A (MAO-A) and monoamine oxidase B (MAO-B), which are
present in mitochondria both within the presynaptic neuron and in other cells, including neurons and glia.
ofNE (Figures 11-33 and 11-34). Thus, presynaptic alpha 2 autoreceptors act as a brake
for the NE neuron and also cause what is known as a negative feedback regulatory signal.
Stimulating this receptor (i.e., stepping on the brake) stops the neuron from firing. This
probably occurs physiologically to prevent overfiring of the NE neuron, since it can shut
itself off once the firing rate gets too high and the autoreceptor becomes stimulated. It is
worthy of note that drugs can not only mimic the natural functioning of the NE neuron
by stimulating the presynaptic alpha 2 neuron but that those which antagonize this same
receptor will have the effect of cutting the brake cable, thus enhancing release ofNE.
Monoamine interactions:
NE regulation of 5HT release
We have shown above that norepinephrine regulates norepinephrine neurons (Figures 11-33
and 11-34) and, in Chapter 10, that 5HT also regulates 5HT neurons (see Figures 10-18
and 10-19). In both cases, the regulation is that of negative feedback inhibition: both
neurotransmitters inhibit their own release.
We now show that NE regulates 5HT neurons and reciprocally, that 5HT also regulates
NE neurons. In the case of NE regulation of 5HT (Figures 11-35 through 11-38), there
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Essential Psychopharmacology
Norepinephrine
Receptors
presynaptic
alpha 2
autoreceptor
postsynaptic
alpha 2C
receptor
alpha 2A
\
postsynaptic
receptor
beta 1 beta 2
receptor
postsynaptic
receptor
alpha 28
beta 3
receptor
receptor
FIGURE 11-32 Norepinephrine receptors. Shown here are receptors for norepinephrine that regulate its
neurotransmission. The norepinephrine transporter (NET) exists presynaptically and is responsible for clearing
excess norepinephrine out of the synapse. The vesicular monoamine transporter (VMAT2) takes norepinephrine up
into synaptic vesicles and stores it for future neurotransmission. There is also a presynaptic alpha 2 auto receptor,
which regulates release of norepinephrine from the presynaptic neuron. In addition, there are several postsynaptic
receptors. These include alpha 1, alpha 2A, alpha 28, alpha 2C, beta 1, beta 2, and beta 3 receptors.
is not only negative feedback inhibition of NE on 5HT release at alpha 2 receptors on
axon terminals, thus acting as a brake on 5HT release (Figures 11-35 and 11-36), but
also positive feedback at alpha 1 receptors at the somatodendritic area, thus acting as an
accelerator of 5HT release (Figures 11-35 and 11-37). Thus, NE has bidirectional control
of 5HT release, depending on whether input to the axon terminal alpha 2 heteroreceptor
or to the somatodendritic alpha 1 receptor predominates (Figure 11-38).
Monoamine interactions: 5HT regulation of NE and DA release
In the other direction, 5HT also regulates NE release, but only as negative feedback at
either 5HT2A or 5HT2C receptors, thus inhibiting NE release (Figures 11-39 and 11-40).
This same serotonergic negative feedback regulation occurs for dopamine release and was
discussed for 5HT2A receptors in Chapter 10 and illustrated in Figures 10-21, 10-24,
and 10-25. Here we show the simultaneous negative feedback regulation of 5HT on both
NE and DA release in the prefrontal cortex due to the actions of 5HT in the brainstem
on 5HT2A receptors (Figure 11-39) or on 5HT2C receptors (Figure 11-40). Tn both
cases, 5HT blocks release of both NE and DA in the prefrontal cortex. In truth, the
regulation of DA release by 5HT at 5HT2A receptors is more complicated than this, but
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alpha 2
adrenergic
presynaptic
auto receptor
NE occupying alpha 2 adrenergic
presynaptic autoreceptor halts
release of NE
FIGURE 11-33A and 8 Alpha 2 receptors on axon terminal. Shown here are presynaptic alpha 2 adrenergic
autoreceptors located on the axon terminal of the norepinephrine neuron. These autoreceptors are "gatekeepers"
for norepinephrine. That is, when they are not bound by norepinephrine, they are open, allowing norepinephrine
release (AL However, when norepinephrine binds to the gatekeeping receptors, they close the molecular gate and
prevent norepinephrine from being released (8).
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Essential Psychopharmacology
NE occupying somatodendritic
alpha 2 adrenergic auto receptor causes a
decrease in firing and a decrease of NE release
B
FIGURE 11-34
Somatodendritic
alpha 2 receptors. Presynaptic alpha 2 adrenergic autoreceptors are also
located in the somatodendritic area of the norepinephrine neuron, as shown here. When norepinephrine binds to
these alpha 2 receptors, it shuts off neuronal impulse flow in the norepinephrine neuron (see loss of lightning
bolts in the neuron in the lower figure), and this stops further norepinephrine release.
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NE-5HT Interactions: NE Regulation of 5HT
11-35 Norepinephrineregulationof serotonin. Norepinephrineregulatesserotoninrelease. It does this
by actingas a brakeon serotoninrelease at alpha 2 receptorson axonterminalsand as an acceleratorof
serotoninrelease at alpha 1 receptorsat the somatodendriticarea.
FIGURE
our discussion here is aimed at providing a background for understanding the actions of
atypical antipsychotics in mood disorders; this is not meant to be a comprehensive review of
all aspects of SHT2A receptor regulation ofDA release. Other evidence suggests that some
SHT2A receptors in some brain areas under certain circumstances can actually facilitate
DA release (as discussed in Chapter 10 and illustrated in Figure 10-31).
A separate circuit also regulates SHT2C inhibition ofDA release in the nucleus accumbens (Figure 11-41). In this case, SHT acts upon GABA neurons in the brainstem, one of
which inhibits the mesolimbic dopamine projection when SHT2C receptors are occupied
(Figure 11-41). SHT actions on a second GABA neuron that projects to prefrontal cortex
result in inhibition of a descending excitatory glutamate projection to the dopamine neuron,
further inhibiting dopamine release in the nucleus accumbens (Figure 11-41).
In summary, there are numerous known interregulatory pathways and receptor interactions among the trimonoaminergic neurontransmitter systems so that they can influence
each other and change the release not only of their own neurotransmitters but also of others
within this system.
The monoamine
hypothesis of depression
The classic theory about the biological etiology of depression hypothesizes that depression
is due to a deficiency of monoamine neurotransmitters. At first, there was a great argument
about whether norepinephrine (NE) or serotonin (S-hydroxytryptamine; SHT) was the
more important deficiency, and dopamine was relatively neglected. Now the monoamine
theory suggests that the entire trimonoaminergic neurotransmitter system may be malfunctioning in various brain circuits, with different neurotransmitters involved depending on
the patient's symptom profile.
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alpha 2
heteroreceptor
lSHT
brake
FIGURE 11-36A and 8 Norepinephrine as a brake on serotonin release. Alpha 2 adrenergic heteroreceptors are
located on the axon terminals of serotonin neurons. When these receptors are unoccupied by norepinephrine,
serotonin is released from the serotonin neuron (A). However, when norepinephrine binds to the alpha 2 receptor
this closes the molecular gate and prevents serotonin from being released (8).
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